PGx7654: Pharmacogenetic investigation of the association of the beta2-adrenergic receptor (ADRB2) Thr164Ile variant with risk of hospitalization due to asthma exacerbations

Trial description: Asthma exacerbations are a major healthcare concern. The discovery of a genetic variant that predicts those most at risk for asthma exacerbations could potentially be used to find a mechanism to prevent, or reduce the incidence of, such exacerbations. Ortega et al., 2014 (PMID 24621682), published data describing an association between the genetic variant rs1800888 (encoding ADRB2 Thr164Ile), where the T allele was associated with increased risk of hospitalization due to asthma exacerbations in non-Hispanic white (NHW) subjects treated with a long-acting beta2-agonist (LABA).Two separate post-hoc pharmacogenetic studies conducted by GlaxoSmithKline (study 204661 and 205064) assessed the association of the ADRB2 Thr164Ile encoding variant with the rate of asthma exacerbations in LABA-treated NHW subjects. In these studies, asthma exacerbations were defined as a worsening of asthma requiring the use of oral/systemic corticosteroids (OCS) and/or hospitalization and/or emergency department visits. For subject on maintenance OCS, an exacerbation requiring OCS was defined as the use of OCS at least double the existing maintenance dose for at least 3 days. The T allele of rs1800888 was not associated with increased asthma exacerbation rate in either study. While there was insufficient number of asthma exacerbation hospitalizations in study 204661, study 205064 found an association between T allele of the ADRB2 Thr164Ile (C>T) variant and increased asthma exacerbation hospitalization risk among LABA-treated NHW subjects with severe asthma who were enrolled in study 201722 (NCT02293265). Study 201722 was an observational non-drug interventional study and exacerbation information was available from medical records for the year prior to enrollment.As a confirmatory study for study 205064, the primary objective of this project, study 205643, is to investigate the association between the T allele of rs1800888 with increased asthma exacerbation hospitalization risk among NHW subjects with severe asthma receiving ICS/LABA-containing regimens who were enrolled in studies 112997and 115588 (NCT01000506 and NCT01691521; with study descriptions and results reported in PMIDs 22901886 and 25199059, respectively). The secondary objective is to determine if there is evidence for the association of the T allele of rs1800888 with increased asthma exacerbation rate in NHW subjects treated with ICS/LABA. Studies 112997 and 115588 were not designed explicitly for this pharmacogenetic analysis. All subjects enrolled in 112997 and 115588 had a medical history of two or more asthma exacerbations in the year prior to enrolling in the studies.